Acute lung injury secondary to smoke inhalation represents an annual market of 100,000 patients and $250 million in health care expenditures. There are no market entrants that address this indication. To meet this unmet need, Inotek is developing a novel patented strategy that employs a sulfhydryl-containing small molecule, mercaptoethylguanidine (MEG). MEG interrupts multiple pathogenic mechanisms identified in smoke inhalation and burn injury, acting as 1) a selective inhibitor of inducible nitric oxide (NO) synthase (iNOS) activity, 2) a scavenger of peroxynitrite, and 3) an inhibitor of the expression of pro-inflammatory cytokines and chemokines. In a Phase I SBIR, we showed that MEG provides dramatic benefit in large animal models of I) smoke inhalation and 2) combined smoke inhalation and burn injury. Administration of MEG following injury markedly attenuated the increases in pulmonary lymph flow, pulmonary hypertension, intrapulmonary shunt fraction, lipid peroxidation, bronchial blood flow, pulmonary edema, and serum nitrite/nitrate concentration. The objectives in Phase II are: (#1): Establish the optimal route of administration of MEG in an ovine model of smoke inhalation injury. We will compare the pharmacodynamics of MEG by aerosol or intravenous routes of administration. (#2): Characterize the chemical stability and degradation products of MEG. We will formulate MEG as a lyophilized powder, according to GMP standards. Utilizing well-established LC-MS protocols, we will identity and quantify impurities and breakdown products after synthesis and at various time-points over 12 months of storage. (#3): Determine the toxicity, bioavailability, pharmacokinetics, and tissue distribution of MEG. The toxicology of aerosolized MEG will be established in three species. Definitive sub-acute 7-day toxicity studies will be performed in rats and dogs and a full behavioral, biochemical, and histopathologic profile obtained. Pharmacokinetic profiles of lung and serum uptake of MEG will be established by LC-MS. In Phase III, Inotek intends to file an IND application for a Phase I FDA-approved clinical trial of MEG for the acute treatment of smoke inhalation induced acute lung injury. PROPOSED COMMERCIAL APPLICATIONS: The annual domestic impact of burn injury and smoke inhalation induced acute lung injury on the health care market is estimated at > $250 million. The worldwide market (developed countries only) is four times larger. Given the absence of a specific, safe, and convenient existing therapy, Inotek anticipates market acceptance to be achieved rapidly, at high levels of penetration, and with a high sustained price point ($1000 per patient). Estimated worldwide gross sales revenues after market entry and maturation (ca. 4 years after FDA approval) equal $250 million (annual).